The Asymmetric Hydrogenation of Heterocyclic Ketones ANTONIO ZANOTTI-GEROSA1, ANDREAS MARC PALMER2 1

CHIRAL TECHNOLOGIES

Antonio Zanotti Gerosa

The asymmetric hydrogenation of heterocyclic ketones ANTONIO ZANOTTI-GEROSA1, ANDREAS MARC PALMER2 1. Johnson Matthey, Catalysis and Chiral Technologies, 28 Cambridge Science Park, Cambridge, CB4 05P, United Kingdom 2. Nycomed GmbH, Dep. of Medicinal Chemistry, Byk-Gulden-Str.2, Konstanz, D-78467, Germany

The following Mitsunobu cyclization step afforded the desired KEYWORDS: homogeneous asymmetric hydrogenation, tricyclic imidazo[1,2-a]pyridines 3 without erosion of potassium-competitive acid blockers, P-CABs. enantiopurity. By the time a robust method for the asymmetric synthesis of ABSTRACT: Potassium-competitive acid blockers (P-CABs) 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines 3 had containing an imidazo[1,2-a]pyridine / benzimidazole scaffold, been established, the search for improved candidates had led respectively were prepared via asymmetric hydrogenation to the structural class of 3,6,7,8-tetrahydrochromeno[7,8-d] of aryl ketone intermediates in the presence of RuCl [(S)-Xyl- 2 imidazoles 6 (Scheme 2). Due to the structural similarity of the P-Phos][(S)-DAIPEN]. The enantioselective synthesis of BYK imidazopyridines 3 and the benzimidazoles 6 the same 405879 was successfully implemented on Kg scale. retrosynthetic strategy was applied (10). The tricyclic benzimidazole BYK 405879 (6b) was selected for further development and multi-Kg amounts of material were required POTASSIUM-COMPETITIVE ACID BLOCKERS (P-CABS) for the short term. At this development stage significant improvements were made with respect to the preparation of The inhibition of the gastric proton pump enzyme (H+/K+-ATPase) the prochiral ketones 8 and the limitations of the catalytic step provides a valuable approach for the treatment of a variety of were overcome by the protection of the phenolic group acid-related diseases (1). Irreversible inhibitors of the H+/ present in the hydrogenation substrates (ketone 11) (11). K+-ATPase (PPIs) have been available for some time but there Despite the introduction of two additional synthetic steps is still unmet medical need (2). Hence, several pharmaceutical (protection/deprotection) the overall yield was significantly companies are engaged in the development of potassium- improved over the medicinal chemistry route. These changes competitive acid blockers (P‑CABs), which, due to their allowed the cost-effective production of BYK 405879 (6b) and different mode of action (reversible inhibition of the gastric the timely delivery of the required amount of API. proton pump enzyme), are expected to overcome some of the limitations observed during the PPI treatment of acid- related diseases (3, 4). The structural class of imidazo[1,2-a]pyridines has been in the focus of P-CAB research for a long time. SCH 28080 (1) (Figure 1) was the clinical prototype of this series (5). The detailed analysis of the possible conformations of Scheme 1. Chirality-setting synthetic steps to imidazopyridines 3. SCH 28080 (1) triggered the discovery of the rigid analog 2 in which an ethylene bridge enforces the required orientation Figure 1. Earlier P-CABs candidates. between the phenyl ring and the imidazo[1,2-a]pyridine system (6) (Figure 1). The systematic study of 7H-8,9-dihydropyrano[2,3-c] imidazo[1,2-a]pyridines resulted in the identification of the carboxamides BYK 311319 (3a) and BYK 357695 (3b) as promising preclinical candidates (Scheme 1). On the other hand, the synthesis of the tricyclic imidazo[1,2-a]pyridines 3 was significantly more challenging than the preparation of Scheme 2. Chirality-setting synthetic steps to benzimidazoles 6. their open chain analogues and an asymmetric synthesis had to be developed (7-9). Homogeneous hydrogenation catalysts ASYMMETRIC REDUCTION OF KETONES BEARING THE

of the general structure RuX2[diphosphine][diamine] offered IMIDAZO[1,2-A]PYRIDINE SKELETON the best solution when applied to the hydrogenation of

intermediate ketone 5, which had already been used for the “Noyori-type” catalysts, RuX2[diphosphine][diamine], reduce synthesis of the racemic analogs of diol 4. substituted aromatic ketones, unsaturated ketones and

40 chimica oggi/Chemistry Today - vol 28 n 4 July/August 2010 41 CHIRAL TECHNOLOGIES

heteroaromatic ketones with very high activity and ASYMMETRIC REDUCTION OF KETONES BEARING stereoselectivity (12). THE 3,6,7,8-TETRAHYDROCHROMENO[7,8-D]IMIDAZOLE SKELETON The advantages over conventional hydride chemistry are remarkable and become more significant the larger the scale When the focus of chemical development was shifted to of the reaction: simplicity of use of the catalysts, minimal 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles 6 (Scheme 2) the requirement for reaction work up, excellent time and volume best reaction conditions developed for imidazo[1,2-a]pyridines efficiency even at low catalyst loadings. were applied but the parent ketone 8a was reduced with full Based on general literature and on commercial conversion only at S/C 500/1 (70°C, 25 bar hydrogen,

availability, RuCl2[(S)-BINAP][(S)-DAIPEN] (Figure 2) was >98 % ee) (10). The addition of water did not give any clear initially chosen for the asymmetric reduction of the advantage and was abandoned for further development on unprotected ketone 5a (Scheme 1) and encouraging this class of substrates. The application of the hydrogenation results were soon obtained (7). procedure to the most interesting candidate of the series (6b, At that time, small-scale hydrogenation screening Ar = 2-methylphenyl) required even higher catalyst loadings, in experiments could not be performed in an effective manner line with the increased steric hindrance of the substrate. at Nycomed. Consequently, it was decided to optimize the Addition of larger amounts of base to increase the reaction hydrogenation reaction in collaboration with Solvias AG, rate resulted in the formation of a reactive enolate species Basel, for the screening of a greater variety of catalytic that attacked the carboxamide moiety of ketone 8, with the systems and Johnson Matthey, Catalysis and Chiral consequent formation of substantial amounts of a side- Technologies (JM CCT), Cambridge, for the specific product (10) that had never been detected in the screening of further “Noyori-type” catalysts. imidazo[1,2-a]pyridines series. At this stage a new, wider i Catalyst RuCl2[PPh3][(Sc,Sm)-Ph2P-Fc-oxa- Pr] (Figure 2) was screen of catalysts based on an high throughput (HTS) tested at Solvias AG, soon to find out that the presence of approach was carried out but did not provide any catalytic

the phenol-pyridine structural motif was incompatible with system superior to RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] (10). the use of such catalyst, completely shutting down catalytic activity. Full conversion was obtained when the phenolic ketone was transformed into the corresponding benzyl ether LARGE SCALE ASYMMETRIC SYNTHESIS OF BYK 405879 (83 % ee at a molar substrate to catalyst ratio, S/C, of 200/1) or the corresponding silyl ether (90 % ee at S/C 400/1) (8). The decision to base the process research on the synthesis of A catalyst screen at Johnson Matthey focused on the use of BYK 405879 pursued in medicinal chemistry required

catalysts of the type RuCl2[diphosphine][diamine] on improvements in three main areas: synthesis of ketone 8b substrate 5a (Scheme 1). The catalyst RuCl2[(S)-Xyl-P-Phos] (Scheme 2), asymmetric hydrogenation, and Mitsunobu [(S)-DAIPEN] (Figure 2) (13), giving >97 % ee, was identified cyclization (11). After considerable efforts in process research as the best candidate for further development. Since acidic it was demonstrated that ketone 8b could be prepared by functionalities such as phenol groups are not compatible alkylation of a Mannich base with ethyl 3-(2-methylphenyl)-3- with the use of Noyori-type catalysts, a stoichiometric oxo-propanoate in excellent purity, a fact of paramount amount of base was added (1.1 equivalents of t-BuOK in importance considering that the enantioselectivity of the t-BuOH) instead of the commonly used sub-stoichiometric following asymmetric hydrogenation step depended on the amount (0.02 to 0.05 equivalents of base to substrate). At purity of the starting material. lower catalyst loading the reaction was found to go to Despite intensive studies no significant improvement of the completion in wet 2-propanol, contrary to the commonly S/C ratio could be achieved in the asymmetric hydrogenation held belief that “Noyori-type” catalysts require anhydrous step. Diol 7b was obtained in good yield (80 %) and optical purity conditions. (94 % ee) only at 200/1 (1.1 equiv. of t-BuOK, c = 0.5 M, 80 bar

A combination of increased substrate concentration and H2, 2-PrOH, t-BuOH, 65-70 C, 20 h). At this stage the reduction of use of high hydrogen pressure (25 bar to 80 bar) finally gave 1 kg of ketone 8b still required 33 g of RuCl2[(S)-Xyl-P-Phos][(S)- access to high conversion at low catalyst loading while DAIPEN]. On the contrary, the hydrogenation of the protected maintaining good enantioselectivity. The reaction was ketone 11b proceeded with excellent enantioselectivity of demonstrated at S/C 5000/1 on small scale and at >96 % ee even at very high S/C ratios (0.1 equiv. of t-BuOK, c = S/C 1000/1 on larger scale (25 g of ketone 5a, 1.1 equiv. of 0.5 M, 70 °C, 18 h). The use of the benzyl-protected benzimidazole

t-BuOK, c = 0.4 M, 80 bar H2, 2-PrOH, t-BuOH, 10 percent of ketone 11b probably suppressed the tendency of the substrate H2O, 65 °C, 22 h, 93 percent isolated yield and 98 % ee). to deactivate the catalyst via chelation to the metal by the Initially, the diol 4a was purified by chromatography. This benzimidazole moiety and the phenolic hydroxy group. As an method not only had obvious scale up problems but also additional advantage the reaction became feasible using did not remove all ruthenium-containing species. The best catalytic amounts of base and the rate of the base-catalyzed isolation protocol involved a crystallization of the crude background reaction was reduced. When a hydrogen pressure alcohol from acetone or acetone / MTBE (>90 percent of 80 bar was applied, clean and quantitative conversion was isolated yield with <10 ppm Ru starting from 90 ppm at achieved up to a S/C ratio of 5000/1 and even at low hydrogen S/C 3000/1 and 55 ppm at S/C 5000/1). pressure (10 bar) the transformation was feasible up to a S/C ratio of 3500/1, indicating that standard pilot plant vessels for hydrogenation could also be used for the reaction instead of the often size-limited high pressure autoclave equipment. At Nycomed a 10 L Premex Hastelloy autoclave was first conditioned by running a ‘sacrificial’ asymmetric reduction of acetophenone

in the presence of RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] in 2-propanol and potassium tert-butylate. Subsequently, the reduction of five 1 kg batches of ketone 11b was then performed at S/C ratios of 1000/1 and 2500/1 and the reactions were worked up by neutralization of the reaction mixture with acetic acid, dilution Figure 2. Catalysts for asymmetric hydrogenation of ketones. with water, and isolation of the crystalline precipitate (Scheme 3).

42 chimica oggi/Chemistry Today - vol 28 n 4 July/August 2010 The combined batches were crystallized from 2-propanol and the alcohol 9b was isolated in 81 percent yield and an optical purity of 98.5 % ee. With this new Scheme 3. Asymmetric hydrogenation of benzimidazole ketone 11. synthetic route, only 1 g of RuCl2[(S)-Xyl-P-Phos] [(S)-DAIPEN] was required for the asymmetric reduction of 1 kg of ketone. Hydrogenolytic cleavage of the benzyl ether 9b with Pd/C easily afforded the diol 7b in 90 % yield. The ruthenium and palladium content of the 5 kg batch of diol 7b was analyzed and values of 11 ppm (Ru) and 27 ppm (Pd) were determined. The Mitsunobu cyclization of the diol 7b to the API BYK 405879 (6b) was accomplished in the presence of diisopropyl diazene-1,2-dicarboxylate and triphenylphosphine. The yields could be improved considerably by using toluene instead of THF as a solvent together with careful control of the temperature of the exothermic reaction. The heavy metal content was reduced further in the course of this reaction and the subsequent purification of the API meeting the specification threshold for total heavy metals of <20 ppm.

CONCLUSIONS

The asymmetric hydrogenation step in the synthetic route to P-CABs was successfully implemented from small-scale catalyst identification to on-time delivery of multi-Kg quantities (14). The key decision to focus on catalytic asymmetric ketone reduction was taken at an early stage and implemented through collaboration of the Nycomed team with Solvias and Johnson Matthey. The project was developed over several years and took advantage of the strengths of the collaborating partners. The research at Johnson Matthey, for instance, focused first on catalyst identification, small-scale optimization, extension of the technology on a wider range of substrates and finally on catalyst supply. This was complementary to the development work carried out at Nycomed from the points of view of research focus, as well as hydrogenation and analytical equipment used. The close collaboration with the technology companies was a success factor, as well as the positive approach taken by Nycomed toward the chemocatalytic approach from the very beginning of the project. In this way, the technology was quickly transferred, implemented and improved at Nycomed. Hydrogenation with ‘Noyori-type’ catalysts offered, in this specific case, the best combination of activity and enantioselectivity within the required timeframe. Despite the significant and ever growing amount of academic publications in the area of asymmetric ketone reduction, the application of procedures developed on simplified model substrates to the highly functionalised molecules of interest to life science industry remains an ongoing challenge. In the present case, the identification of the best catalyst was relatively straightforward and the catalyst RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] worked across a range of substrates. On the contrary, the optimization of the reaction was time consuming: two synthetic routes were examined (using the protected and unprotected phenol) and reaction conditions had to be optimized for each substrate. By introducing the benzyl protecting group into the ketone substrate, the asymmetric reduction could be performed at reduced catalyst loading with high yield and optical purity. These advantages more than compensated for the longer synthetic route.

REFERENCES AND NOTES

1. M.L. Schubert, D.A. Peura, Gastroenterology, 134, pp. 1842-1860 (2008). 2. K.R. DeVault, N.J. Talley, Nature Reviews Gastroenterology Hepatology, 6, pp. 524-532 (2009). 3. M. Bamford, Progress in Medicinal Chemistry, 47, pp. 75-162 (2009). 4. J.M. Shin, G. Sachs, Expert Review Clin. Pharmacol., 2, pp. 461-468 (2009). 5. J.J. Kaminski, J.M. Hilbert et al., J. Med. Chem., 30, pp. 2031-2046 (1987). 6. J.J. Kaminski, C. Puchalski et al., J. Med. Chem., 32, pp. 1686-1700 (1989). 7. A.M. Palmer, B. Grobbel et al., J. Med. Chem., 50, pp. 6240-6264 (2007). 8. A.M. Palmer, U. Nettekoven, Tetrahedron: Asymmetry, 18, pp. 2381-2385 (2007). 9. A.M. Palmer, A. Zanotti-Gerosa et al., Tetrahedron: Asymmetry, 19, pp. 1310-1327 (2008). 10. A.M. Palmer, V. Chiesa et al., Tetrahedron: Asymmetry, 19, pp. 2102-2110 (2008). 11. A.M. Palmer, M. Webel et al., Org. Process Res. Dev., 12, pp. 1170-1182 (2008). 12. R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 40, pp. 40-73 (2001). 13. The P-Phos ligand family was introduced by Prof. A.S.C. Chan: J. Wu, A.S.C. Chan., Acc. Chem. Res., 39, pp. 711-720 (2006). 14. An account of the project is published in Asymmetric Catalysis on Industrial Scale, 2nd edition, editors: Blaser, Federsel – VCH-Wiley (2010).